PROJECT ABSTRACT Topical delivery of therapeutic agents across skin offers key benefits in improving patient compliance, lowering systemic drug exposure, and enabling tunable delivery. Therapeutic macromolecules such as antibodies or aptamers enables better efficacy, less off-target effects, and longer half-life comparing to small molecules, and may unlock tremendous additional value if delivered topically. Multiple approaches have been developed for transdermal delivery of macromolecules, but have so far met with commercial and/or clinical setbacks. In consequence, so far topical delivery is critically limited to small molecules that possess particular physicochemical properties to diffuse across the skin barrier. There is a significant unmet need for a platform technology that can effectively deliver therapeutic macromolecules across the skin. Aptamers are single stranded oligonucleotides that bind to molecular targets with high potency and specificity, similar to antibodies. Comparing to antibodies, aptamers are a unique fit for topical delivery thanks to its small size, superior stability, and lack of immunogenicity. We propose to develop the first platform to effectively deliver therapeutic aptamers across the skin, and enable safer and more efficacious treatment of skin diseases. If successful, this platform has the potential to enable topical delivery of aptamers targeting many targets and disease indications.